HACE1 E3结合酶调解了mTOR信号复合体的RAC1依赖的控制
Busra Turgu1,2, Amal El-Naggar1,3,4, Melanie Kogler5
1Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
EMBO reports
|October 17, 2023
概括
通过准RAC1,E3泛基因酶HACE1抑制瘤,RAC1破坏了mTOR信号复合体的稳定. 这一发现揭示了控制mTOR活动的全新的,依赖于ubiquitin的途径.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- HACE1 (HECT域E3泛素化酶1) 是一种瘤抑制剂,其机制不完全定义.
- 哺乳动物的拉巴胺素 (mTOR) 途径的标在细胞生长中至关重要,并且在癌症中经常失调.
研究的目的:
- 为了研究HACE1和mTOR信号之间的联系.
- 阐明HACE1调节mTOR活动的机制.
主要方法:
- 同免疫沉测试检测蛋白质相互作用.
- 乌比基化试验用于评估蛋白质修饰.
- 西方涂抹测量蛋白质水平.
- 细胞和体内模型 (包括小鼠异种移植) 用于研究瘤发育和信号通路活性.
主要成果:
- 在mTOR相关复合体内,HACE1直接与Ras相关的C3肉毒毒素基质1 (RAC1) 相互作用并无处不在.
- 这种无处不在导致RAC1的蛋白质体降解,从而降低mTORC1和mTORC2的稳定性和活性.
- 缺少HACE1会增强mTORC1/2的活性,而RAC1的抑制会恢复这种活性.
- 在体内,Rac1删除在HACE1缺乏,Kras驱动的肺瘤中逆转了增强的mTOR表达.
结论:
- HACE1通过向RAC1进行降解,作为mTOR信号的负调节器.
- 这种机制突显出一种新型的依赖于乌比奎的途径,控制mTOR复合物的活性和瘤抑制.
- 通过RAC1破坏mTOR的HACE1的作用为具有mTOR通路失调的癌症提供了潜在的治疗点.
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